Enthusiasm for anti-tumor immunotherapy has increased dramatically with the clinical success of immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) across diverse tumor types. Checkpoint inhibitors release normal immune homeostatic mechanisms that impair the anti-tumor immune response. Despite the promise of this approach, the majority of patients do not achieve long- term remission and many cancer types do not respond to this type of therapy, felt to be due in part to inadequate education of the immune system to the relevant tumor-associated antigens. Priming the immune system during checkpoint inhibition therapy to better recognize tumor-associated antigens (TAAs), using cancer vaccines, is an attractive option for improving outcomes. A major challenge for conventional cancer vaccines, however, is their potency. To address this, TAAs have been delivered using a protein nanoparticle platform, E2, and this strategy has been shown to elicit antigen-specific destruction of cancer cells and to significantly extend survival time for tumor-bearing mice. The overall hypothesis of this proposed work is that by combining the synergistic mechanisms of increasing antigen-specific effects using the E2 nanoparticle, while simultaneously releasing the brakes on immune checkpoints, a better outcome will be achieved which prolongs survival time and sustains anti-tumor immune responses. To test this hypothesis, we propose the following specific aims: (1) Elucidate nanoparticle design and delivery strategies that will increase anti-tumor responses, and determine the mechanisms of elicited anti-tumor activity; (2) Examine the scope of E2-based vaccine efficacy by confirming activity in another tumor model in vivo and evaluating human immune responses ex vivo; and (3) Evaluate the therapeutic combination of E2- based vaccine formulations with a prototypical checkpoint inhibitor, anti-PD1, for enhanced anti-tumor immune response. This work will evaluate whether more effective immunotherapy can be achieved by increasing tumor antigen-specific responses (via E2 nanoparticle vaccines) while simultaneously blocking the checkpoints to remove immune suppression (via immune checkpoint inhibition). These studies will generate general principles for improving cancer treatment using such combination therapies. Ultimately, it can potentially provide a more effective therapeutic strategy applicable for cancer states that are conventionally difficult to treat.